ORGANIC LETTERS
Efficient and Stereoselective Access to the Polyol Fragment C9-C16 of Ansamycin Antibiotics
2009 Vol. 11, No. 16 3542-3545
Michel Obringer, Marie Barbarotto, Sabine Choppin, and Franc¸oise Colobert* Laboratoire de ste´re´ochimie associe´ au CNRS, UMR 7509, UniVersite´ de Strasbourg, ECPM, 25 rue Becquerel, 67087 Strasbourg Cedex 2, France
[email protected] Received June 2, 2009
ABSTRACT
Efficient synthesis of the fragment C9-C16 bearing the anti,syn stereotriad of ansamycin antibiotics is described. Key steps for controlling the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction of a β-ketosulfoxide.
Isolation from microbial sources (Streptomycines generally) and structure elucidation of an important class of complex macrolactam antibiotics, the ansamycins (mycotrienins),1 has been reported in the last two decades. These secondary metabolites are very attractive because of their powerful biological activity, for example, antibacterial, antifungal, or antitumor properties. The ansamycin class of natural products includes mycotrienins (or ansatrienins) I (1a) and II (2a),2 trienomycin A (3a),3 cytotrienin A (2b),4 and thiazinotrieno(1) Wrona, I. E.; Agouridas, J.; Panek, J.S. C. R. Chimie 2008, 11, 1483. (2) Sugita, M.; Hiramoto, S.; Ando, C.; Sasaki, T.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 38, 799, and references cited therein. (3) (a) Nomoto, H.; Katsumata, S.; Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1989, 42, 479. (b) Blagg, B. S.J.; Peng, W. Org. Synth. 2006, 8, 965. (4) (a) Zhang, H. P.; Kakeya, H.; Osada, H. Tetrahedron Lett. 1997, 38, 1789. (b) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamura, T.; Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Ang. Chem., Int. Ed. 2008, 47, 6657. (5) Hosokawa, N.; Yamamoto, S.; Uehara, Y.; Hori, M.; Tsuchiya, K. S. J. Antibiot. 1999, 52, 485, and references cited herein. 10.1021/ol901144j CCC: $40.75 Published on Web 07/22/2009
2009 American Chemical Society
Figure 1. Members of the triene-ansamycins group.
mycin (4a)5 (Figure 1). More recently, quinotrierixin (1a with a SCH3 on the quinone ring), demethyltrienomycins A and B, and demethyltrienomycinol (without a methyl at C14) were isolated from the culture broth of Streptomyces species
PAE37 and were found to have cytocidal activity against HeLa cells.6 All these compounds are characterized by a 21membered cyclic lactam including a (E,E,E)-triene and four chiral centers. A series of SAR studies were performed to screen the most active part of the triene ansamycins. These results indicate that the stereotriad C11-C13, the CH3 group at C14, and the OCH3 group at C3 are essential.6,7 Absolute and relative stereochemistry of the stereogenic centers of these ansamycins have been determined or assigned by Smith and co-workers through careful degradative and spectroscopic methods.8 To date, only Smith, Panek, and very recently Hayashi have reported the total synthesis of trienomycin,9 mycotrienin,10 thiazinotrienomycin,11 and cytotrienin A4b as well as the macrocyclic core of cytotrienin.12 More recently, Kirschning et al. reported a multigram scale synthesis of the ansatrienol derivative.13 In relation with a program devoted to asymmetric synthesis mediated by sulfoxides,14 we have recently described a highly stereoselective Reformatsky-type reaction of chiral non racemic R-bromo-R′-sulfinyl ketones with aldehydes in the presence of SmI2.15 In this paper, we describe the synthesis of the C9-C16 unit 5 of ansamycins bearing the anti,syn stereotriad C11-C13. (6) (a) Kawamura, T; Tashiro, E.; Yamamoto, K.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 303. (b) Kawamura, T; Tashiro, E.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 312. (7) (a) Funayama, S.; Anraku, Y.; Mita, A.; Yang, Z.-B.; Shibata, K.; Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1988, 41, 1223. (b) Tashiro, E.; Hironiwa, N.; Mitsuhiro, K.; Futamura, Y.; Suzuki, S.-I.; Nishio, M.; Masaya, I. J. Antibiot. 2007, 60, 549. (c) Kawamura, T; Tashiro, E.; Yamamoto, K.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 303. (d) Kawamura, T; Tashiro, E.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 312. (8) (a) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J. J. Am. Chem. Soc. 1990, 112, 7425. (b) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Komiyama, K.; Omura, S. J. Am. Chem. Soc. 1996, 118, 8308. (9) (a) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1995, 117, 10777. (b) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1996, 118, 8316. (10) (a) Panek, J. S.; Masse, C. E. J. Org. Chem. 1997, 62, 8290. (b) Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am. Chem. Soc. 1998, 120, 4123. (11) (a) Smith, A. B., III; Wan, Z. Org. Lett. 1999, 1, 1491. (b) Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738. (12) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525. (13) Kashin, D.; Meyer, A.; Wittenberg, R.; Scho¨ning, K.-U.; Kamlage, S.; Kirschning, A. Synthesis 2007, 304. (14) Overviews: (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717. (b) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´, G. ARKIVOC 2003, 7, 328. (c) Fernandez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651. Recent work: (c) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem. 2005, 3334. (d) Broutin, P.-E.; Colobert, F. Org. Lett. 2005, 7, 3737. (e) Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113. (f) Colobert, F.; Ballesteros-Garrido, R.; Leroux, F. R.; Ballesteros, R.; Abarca, B. Tetrahedron Lett. 2007, 48, 6896. (g) Colobert, F.; Choppin, S.; Ferreiro-Mederos, L.; Obringer, M.; Luengo Arratta, S.; Urbano, A.; Carren˜o, M. C. Org. Lett. 2007, 9, 4451. (h) Carren˜o, M. C.; Hernandez-Torres, G.; Urbano, A.; Colobert, F. Eur. J. Org. Chem. 2008, 12, 2035. (15) (a) Obringer, M.; Colobert, F.; Neugnot, B.; Solladie´, G. Org. Lett. 2003, 5, 629. (b) Obringer, M.; Colobert, F.; Solladie´, G. Eur. J. Org. Chem. 2006, 1455. (16) Early work: (a) Carren˜o, M. C.; Garcı´a Ruano, J. L.; Martı´n, A.; Pedregal, C.; Rodrı´guez, J. H.; Rubio, A.; Sa´nchez, J.; Solladie´, G. J. Org. Chem. 1990, 55, 2120. Recent examples: (b) Lanners, S.; Hassan, N.-A.; Salom-Roig, X. J.; Hanquet, G. Angew. Chem. Int. Ed. 2007, 46, 7086. (c) Raghavan, S.; Krishnaiah, V. Tetrahedron Lett. 2006, 47, 7611. (d) Cardellicchio, C.; Omar, O. H.; Naso, F.; Capozzi, M. A. M.; Capitellic, F.; Bertolasi, V. Tetrahedron: Asymmetry 2006, 17, 223. (e) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966. Org. Lett., Vol. 11, No. 16, 2009
One synthetic key issue of the ansamycin is the stereocontrol of the stereotriad C11-C13. Using our Reformatsky-type reaction between R-bromo-R′-sulfinyl ketone 6 and the aldehyde 7 as well as the well-established DIBALH or Lewis acid/DIBALH diastereoselective reduction16 of the corresponding β-keto sulfoxide 8, we report a highly stereoselective access to the stereotriad (Scheme 1). To facilitate
Scheme 1. Retrosynthesis toward the C9-C16 Unit 5 of Ansamycin
elucidation of mechanism of action of ansamycins, the development of a methodology allowing the synthesis of some stereoisomers of the stereotriad is highly important. With our methodology, four diastereomers of the stereotriad could be easily accessible depending on the absolute configuration of the sulfinyl moiety.
Scheme 2. Synthesis of the Aldehyde 7
The synthesis of the aldehyde 717 depicted in Scheme 2 began with the formation of the diethyl acetal of ethyl pyruvate in the presence of triethyl orthoformate in concentrated sulfuric acid. Reduction of the ester moiety with LiAlH4 followed by transacetalization in the presence of diethylene glycol afforded the dioxolane derivative which was then submitted to a Moffatt-type oxidation to give the aldehyde 7 in 52% overall yield. (17) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996, 37, 3881. 3543
We applied our SmI2-promoted Reformatsky-type reaction between R-bromo-R′-tert-butylsulfinyl ketone 6 synthesized as previously reported15a and the aldehyde 7, and we obtained the Reformatsky adduct 8 in excellent syn diastereoselectivity18 and good yield (Scheme 3).
Scheme 4. Obtaining the Syn-Anti Stereotriad
Scheme 3. Reformatsky-Type Reaction between 6 and 7
To confirm the absolute configuration of the major stereoadduct, after chromatographic separation and crystallization, suitable crystals were obtained and the structure (3R,4R)-8 was determined by X-ray analysis (Figure 2).
aldehyde 11, which was then submitted to a Wittig reaction with Ph3PdCH2 in THF to give the corresponding olefin 12 in 88% yield. Further regioselective hydroboration of 12 with 9-BBN in THF followed by treatment with NaOH and H2O2 afforded the alcohol 13 in 90% yield which was protected as a silylated ether 14 (Scheme 5).
Scheme 5. Synthesis of the Methyl Ketone 16
Figure 2. ORTEP plot of (3R,4R)-8. Hydrogen atoms are omitted for clarity.
In order to obtain the (2R,3R,4R,RS) stereotriad of ansamycins, we performed the diastereoselective reduction of 8 with DIBALH in the presence of Yb(OTf)3 followed by protection of the resulting 1,3-diols by a silylated bridge19 giving after flash chromatography the enantiopure (2R,3R,4R,RS)-10 [[R]20D ) +34.8 (c 0.45, CHCl3)] whose stereochemical assignment was controlled by NOESY experiments (Scheme 4). It should be pointed out that the stereoisomer (2S,3R,4R,RS) was easily obtained by reduction with DIBALH only, and both diastereomers (2R,3S,4S,SS) and (2S,3S,4S,SS) could be efficiently synthesized using the enantiomer (S) of the sulfinyl moiety. Treatment of the enantiopure compound 10 under Pummerer conditions20 afforded after flash chromatography the (18) Determined by proton NMR analysis of the product on the basis of our previous results.15 (19) (a) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871. (b) Toshima, K.; Jyojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.; Matsumura, S. J. Org. Chem. 2001, 66, 1708. (20) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881. 3544
In order to obtain the methyl ketone 16 which will be transformed into the vinylic ester 5, we had to perform a selective deprotection of the dioxolane 14 in the presence of the silylene bridge. The first attempt using PPTS in acetone and water afforded only the deprotection of the TBDMS Org. Lett., Vol. 11, No. 16, 2009
ether. Therefore, we tried the deprotection on the free alcohol 13 with PPTS in acetone/water at reflux or with acetic acid/ water at room temperature, but no reaction occurred. Nevertheless, more acidic conditions such as p-toluenesulfonic acid in water at room temperature or use of CAN21 led to the deprotection of the dioxolane as well as the deprotection of the silylated bridge. Finally, formic acid in presence of CuSO422 in a mixture of CH2Cl2 and hexane (1/1) afforded the methyl ketone 15 in 65% yield whose primary alcohol was then silylated to give 16 (Scheme 5). Starting from the methyl ketone 16, we used the Smith8b procedure to obtain the methyl-substituted double bond with Z selectivity. The kinetic enolate of 16 was obtained by treatment with sodium bis(trimethylsilyl)amide and trapped with diethyl chlorophosphate to give the corresponding enol phosphate. Elimination induced by t-BuLi provided the terminal alkyne 17 in 73% yield. Treatment of 17 with t-BuLi and methyl chloroformiate afforded 18. Finally, methyl cuprate (Me2CuLi) addition was performed in THF at -20 °C giving in 61% yield the desired Z olefin 5. The stereochemistry of the double bond was controlled by NOESY experiments considering the interaction between H15 and the adjacent methyl group (Scheme 6). In conclusion, our strategy based on the stereoselective Reformatsky-type reaction followed by the reduction of β-ketosulfoxides has been exemplified by the enantiopure synthesis of the stereotriad C11-C13 of ansamycin antibio(21) (a) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207. (b) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Marko´, I. Tetrahedron Lett. 1999, 40, 1799. (22) Aubert, C. Gotteland, J. P. Malacria, M. J. Org. Chem. 1993, 58, 4298. I would like to thank Corinne Aubert for this excellent suggestion.
Org. Lett., Vol. 11, No. 16, 2009
Scheme 6. Synthesis of the Z Olefin 5
tics. The asymmetric synthesis of C9-C16 fragment 5 has been achieved in 11 steps and an overall yield of 6%. Total synthesis of trienomycinol 3 (with R ) H) is currently underway in our laboratory. Acknowledgment. This work was supported by the CNRS and Ministe`re de la Recherche. M.O. and M.B. thank the Ministe`re de la Recherche for a fellowship. Supporting Information Available: Experimental procedures and data for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL901144J
3545
